tbuckley/cabot-search huggingface dataset:
PATH-41. THE DEVELOPMENT OF PRIMITIVE NEURONAL COMPONENT AT FIRST PROGRESSION OF MALIGNANT GLIOMA, A CASE SERIES
Authors: Tresa McGranahan, Katelyn Costanza, Patrick Cimino
Journal: Neuro-Oncology (2022)

Abstract A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). These tumors are associated with higher rates of isocitrate dehydrogenase (IDH) mutations and increased responsiveness to platinum-based therapies, however they are also associated with a high rate of cerebrospinal fluid (CSF) dissemination. We review four patients treated at our institution with a prior diagnosis of malignant glioma who were found to have GBM-PNC at resection of recurrent disease and evaluate the clinical significance of the development of a primitive neuronal component. Of the 4 patients, 3 had previously been diagnosed with glioblastoma with a disease-free interval after radiation and temozolomide of 17.8 years, 2.4 years, and 1.6 years. The 4th patient was diagnosed 2 years prior with a WHO grade 2 IDH mutant astrocytoma and had only been treated surgically prior to disease progression. At recurrence, all patients developed cystic masses adjacent to prior surgical site in frontal lobe and/or temporal lobe. While no patients had spinal cord symptoms, as a result of the primitive component found at re-resection 3 out of 4 patients underwent spinal cord imaging. Two patients were found to have cauda equina enhancement favored to represent CSF dissemination. This is in line with the 40% CSF dissemination reported in other case series of diagnosis of GBM-PNC and far greater than 1.1% reported for glioblastoma. In this case series, the of development of primitive neuronal component at malignant glioma recurrence was associated with radiographic appearance of a cystic mass with significant vasogenic edema as well as high rates of CSF dissemination. The clinical implication of platinum responsiveness will also be presented.
EXTH-09. HSP90 INHIBITION AS A NOVEL THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Stefanie-Grace Sbergio, Javal Sheth, Laura Canty, Sanja Pajovic, Arun Anguraj Vadivel, Sheyenne Carette, Robert Siddaway, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor. The mean age of onset is 7-9 years with a median survival of 9 months following diagnosis. Histone 3 (H3) mutations (H3K27M) have been identified in approximately 80% of patients, representing an intriguing target, but how to do this is unclear. To address this, we performed a synthetic lethality drug screen of over 2400 compounds on isogenic cells expressing H3K27M and empty vector. 37 drugs were synthetically lethal with H3K27M, including HSP90 inhibitors. In cancer, HSP90 has a higher isoelectric point which can be targeted specifically by PU-H71. Using PU-H71, HSP90 complexed with oncogenic clients can be inhibited to reduce tumor cell viability. We tested PU-H71 on primary patient derived DIPG lines demonstrating caspase-3/7 mediated cell death within 24 hours (n=3) and an IC50 of 100-200 nM (n=5) at 72 hours. HSP90 is a molecular chaperone that supports protein activation and localization; thus, its inhibition may allow simultaneous targeting of multiple oncogenic pathways. To determine which pathways are targeted in DIPG we used PU-H71-conjugated beads to pull-down HSP90 complexed with client proteins. LC-MS/MS characterization of the HSP90 interactome from three DIPG cell lines (SU-DIPG XVII, SU-DIPGXXV, SU-DIPG 50) identified 339 overlapping proteins including MAPK3, SMS, SRM, CTSP1, OAT, GMPS, and PYG. Pathway enrichment analysis highlighted roles in cell cycle regulation and metabolic processes. Treating DIPG with PU-H71 successfully reduced tumor cell viability but PU-H71 has poor brain penetration. To overcome this, a molecular isoform of PU-H71 has been developed, PU-HZ151, which will be used to test the in vivo efficacy of HSP90 inhibition for DIPG.
EXTH-67. PRECLINICAL ASSESSMENT OF THE EFFICACY OF MPT0B640, AN ORALLY BIOAVAILABLE SMALL MOLECULE HSP90 INHIBITOR, AGAINST GLIOMAS
Authors: Pratibha Sharma, Jihong Xu, Xiaohua Chen, Longfei Huo, Zhenlin Ju, Ziyi Li, Kechen Ban, Ethan Seah, Deepa Sampath, Vinay Puduvalli
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Heat-shock protein 90 (HSP90), an evolutionary conserved protein, is a key member of the epichaperome complex involved in maintenance of protein homeostasis during non-stress and stress conditions. It is overexpressed in gliomas and supports tumor cell survival and resistance. Hsp90 inhibition can impact several pathways essential for glioma cell survival and overcome tumor heterogeneity. Here, we examined the activity and toxicity profile of MPT0B640, an orally bioavailable Hsp90 inhibitor, against gliomas and its ability to cross the blood-brain barrier (BBB). METHODS Using genetically heterogeneous glioma stem-like cell (GSC) lines, we determined the effects of MPT0B640 on cell proliferation (Cell Titre Glo assay), apoptosis induction and cell cycle changes (flowcytometry; AnnexinV/PI staining), and alterations in protein expressions (western blot and reverse-phase protein array, RPPA assays). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed in non-tumor bearing mice to assess BBB permeability and antitumor effects of MPT0B640. RESULTS MPT0B640 inhibited proliferation of both adherent (LN229, A172, U251-HF) and patient-derived GSCs (GSC262, GSC811, GSC11, GSC23, GSC20 and GSC272) in a dose- and time-dependent fashion with an IC50 range of 50-1000 nM. MPT0B640-treated cells underwent apoptosis and/or cell cycle arrest with downregulation of pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6. PK/PD studies showed increased HSP70 expression (a marker of Hsp90 inhibition) and detectable levels of drug in brain specimens from non-tumor bearing mice after a single dose of MPT0B640, indicating BBB permeability and target inhibition of the agent. Results of ongoing animal studies assessing drug toxicity and animal survival with MPT0B640 will be presented. CONCLUSIONS MPT0B640 is a potent HSP90 inhibitor that has potent antitumor activity against genetically heterogeneous gliomas in vitro, effectively crosses the intact BBB and demonstrates target inhibition warranting further investigation for treatment of gliomas.
STEM-23. SLOW CYCLING CELL RNA BASED T CELL THERAPY TO PREVENT RECURRENCE IN GBM
Authors: Mariana Dajac, Cole Conforti, Guimei Tian, Ginger Moore, Catherine Flores, Jianping Huang, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM), the most common primary malignancy of the central nervous system (CNS), is almost universally fatal due to inevitable recurrence despite aggressive therapeutics. Considering the infiltrative nature of GBM, targeting residual cells after surgical tumor resection is challenging. Development of effective novel adjuvant therapies against drivers of disease recurrence is of imperative priority. Anticancer treatments most effectively eliminate rapidly dividing cells but spare dormant or infrequently dividing populations. Multiple studies have reported in numerous cancers the existence of slow-cycling cells (SCCs) that are refractory to therapies. Our laboratory identified SCCs in high-grade glioma, which represents an enriched reservoir of highly infiltrative and treatment-resistant cancer propagating cells known to drive recurrence. An effective approach to specifically eliminate this cell population is urgently required to limit recurrence and improve survival. Importantly, these cells reliably defined a cellular niche characterized by definite potentially immunogenic neoantigens, which can serve as immune targets. Our ultimate goal is to leverage the power of adoptive cellular therapy (ACT) to recognize GBM SCC-derived antigens to achieve robust tumor control through targeting of these critical drivers of recurrence. Our data revealed that dendritic cells electroporated with slow-cycling cell RNA successfully primed T cells to recognize and target glioma treatment resistant cells. These experiments demonstrated that slow cycling cell-specific T cells (SCC-T cells) exhibit enhanced activation when in presence of treatment-resistant tumor cells as shown by increased CD8 differentiation, amplified effector and memory differentiation compared to total tumor RNA-specific T cell and control groups. Additionally, SCC-T cells presented the highest anti-tumor activity, as demonstrated by the greatest decrease of tumor cell proliferation and increase of T cell apoptosis. Together these results demonstrate the efficacy and superiority of SCC-based immunotherapy platform to target treatment-resistant glioblastoma cells.
ANGI-07. THE DUAL ROLE CD97 PLAYS IN GLIOBLASTOMA INVASION AND PROLIFERATION
Authors: Tania Slepak, Daniel Eichberg, Manuela Guyot, Winston Walters, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Increased levels of adhesion G Protein-Coupled Receptor(GPCR) CD97 have been detected in multiple metastatic cancers. Glioblastoma(GBM), also overexpress this receptor, and its levels positively correlate with more aggressive GBM invasion. Here, using primary human GBM cells we investigated the effects of CD97 knockdown and overexpression in-vitro and in-vivo. METHODS CD97 consists of two distinct domains: the large extracellular fragment interacting with ECM and other cell surface receptors and the GPCR core that activates heterotrimeric G Proteins G12/13. To investigate the mechanism of action of CD97, we generated a CD97 knockdown (shCD97) and overexpression (CD97-WT) constructs. Additionally, we generated two functional mutants: a constitutively active mutant lacking the N-Terminus (dNTF) and dominant-negative mutant (H436A) that cannot activate G-Proteins downstream. Glioma Stem Cells(GSC) were transduced by control and CD97 lentiviral constructs and implanted into mouse brains. Once tumors formed the brains were harvested, sliced, and immunostained to evaluate invasion and proliferation. Comparing mutants to control, dunnett’s multiple comparisons test was used for statistical analysis. RESULTS Similar to CD97-WT, we found that both dNTF and H436A, increase tumor volume(p&amp;lt; 0.05). In contrast, the shCD97 mutant decreased tumor size(p&amp;lt; 0.05). Interestingly, only dNTF significantly increased tumor cell proliferation(p&amp;lt; 0.005), yet CD97-WT and H436A affected proliferation of non-tumor cells in the tumor bulk, indicating that this process requires the N-Terminus Fragment. In addition, over-expression of CD97-WT dramatically increases tumor invasion along myelinated fibers of corpus collosum, and tumor spread in the brain tissue(p&amp;lt; 0.05). Yet, the H436A mutant produced large, compact, and non-invasive tumors with sharp borders(p&amp;lt; 0.05) indicating that cell migration requires activation of G12/13. Surprisingly, immunostaining revealed that CD97 knockdown cells displayed invasive phenotype. CONCLUSIONS Our results demonstrate the dual role CD97 plays in GBM invasion and proliferation, alluding to the molecular mechanisms that can potentially be targeted in GBM treatment.
QLTI-10. COST-EFFECTIVENESS OF SCRAMBLER THERAPY (CALMARE®) FOR THE TREATMENT OF CHRONIC CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Authors: Neal Prakash
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Acute chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious consequence of cancer treatment. However, for up to 30% of patients, CIPN persists beyond six months of completing chemotherapy, and is transformed to chronic (c)CIPN. Scrambler therapy (ST) is a therapeutic modality with emerging evidence supporting its ability to diminish CIPN symptoms, however, low reimbursement limits patient access to this potentially curative therapy. METHODS Data was from a convenience sample of 24 CIPN patients (with symptoms between 1-240 months after platinum-based, taxane, or combination chemotherapy) completing 10 sessions of ST using the Calmare® device in the City of Hope Outpatient Physical Therapy Department. Patients were treated for ~45 minutes per session over 10 sessions. Patients received a standardized assessment pre- and post ST that included: EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20), mono-filament testing, pain intensity numerical rating scale, numbness scale, extensor hallicus longus strength, Timed Up and Go, Romberg, and single leg balance. RESULTS Significant changes were seen in post-treatment assessment of quality of life as measured by the QLQ-CIPN-20 and numbness scale. Post-treatment QLQ-CIPN-20 total scores decreased by an average of 7.1 points (n= 24, p&amp;lt; .01). Numbness in the left lower extremity decreased by an average of 1 point of the 0-4 point scale (n=24, p=.0007) and 1.09 points on the right lower extremity (n=24, p &amp;lt; .0004). There was a trend towards improvements in pain, monofilament testing, single leg balance, and Romberg test. Reimbursement for ST did not cover the costs to administer the therapy. CONCLUSION For patients with CIPN, scrambler therapy improves numbness and improves quality of life measures. However, reimbursement for ST did not cover the costs. Ways to improve this disparity are discussed.
NCOG-37. MICROSTRUCTURAL CEREBELLAR INJURY IS ASSOCIATED WITH PROCESSING SPEED DECLINE IN ADULTS WITH PRIMARY BRAIN TUMORS: IMPLICATIONS FOR COGNITIVE PRESERVATION
Authors: Mia Salans, Roshan Karunamuni, Soumya Unnikrishnan, Alex Qian, Michael Connor, Suma Gudipati, Anthony Yip, Minh-Phuong Huynh-Le, Michelle Tibbs, Anny Reyes, Alena Stasenko, Adam Schadler, Carrie McDonald, Jona Hattangadi-Gluth
Journal: Neuro-Oncology (2022)

Abstract PURPOSE We investigated associations between imaging biomarkers of cerebellar injury and neurocognitive function among primary brain tumor patients receiving partial brain radiotherapy (RT). METHODS On a prospective trial, 65 patients underwent volumetric brain MRI, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment pre-, 3, 6, and 12 months post-RT. Delis-Kaplan Executive Function System Trail Making [DKEFS-TM] Visual Scanning and Number and Letter Sequencing and Wechsler-Adult Intelligence Scale-IV [WAIS] Coding subtests evaluated PS. Cerebellar regions of interest (ROIs) were autosegmented, including cortex and white matter (WM). Supratentorial cortical and WM structures subserving the above cognitive domains were also autosegmented. Supratentorial PS-associated ROIs included the posterior, mid-posterior, central, mid-anterior, and anterior corpus callosum along with the bilateral intrahemispheric WM. Volume (cm3) was measured in all ROIs at each timepoint. Diffusion biomarkers (fractional anisotropy [FA] and mean diffusivity [MD]) were measured in all WM structures at each timepoint. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If found to be associated, cerebellar biomarkers were subsequently evaluated as predictors of cognitive scores controlling for domain-specific supratentorial ROI biomarkers. RESULTS Left (p=0.04) and right (p&amp;lt; 0.001) cerebellar WM volume declined over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Left cerebellar cortex atrophy correlated with worse DKEFS-TM Number (p=0.01) and Letter (p=0.01) Sequencing scores. Right cerebellar cortex atrophy correlated with worse DKEFS-TM Visual Scanning (p=0.02) and Number (p=0.03) and Letter (p=0.02) Sequencing scores. Greater right cerebellar WM MD correlated with worse DKFS-TM Visual Scanning performance (p=0.03). These associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers. CONCLUSION Biomarkers of cerebellar injury correlated with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Cerebellar dose avoidance may preserve PS.
PATH-46. COMPUTATIONAL HISTOPATHOLOGY INFORMED RAPID TARGETED NANOPORE SEQUENCING ENABLES AFFORDABLE NEXT DAY REPORTING OF COMPREHENSIVE MOLECULAR MARKERS FOR CNS TUMOUR DIAGNOSTICS
Authors: Areeba Patel, Helin Dogan, Alexander Jung, Zaira Seferbekova, Alexander Payne, Michael Ritter, Daniel Schrimpf, Damian Stichel, Stefan Hamelmann, Christina Blume, Philipp Euskirchen, Violaine Goidts, Martin Sill, Stefan Pfister, Matthew Loose, Wolfgang Wick, Andreas von Deimling, David T Jones, Matthias Schlesner, Moritz Gerstung, Felix Sahm
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Integrative brain tumour diagnostics indisputably requires comprehensive reporting of molecular markers. The 2021 WHO classification of central nervous system (CNS) tumours substantially increased the set of markers for routine evaluation, with greater significance to DNA methylation analysis in diagnostics. Limited by investment and batching, smaller labs and clinics might suffer major delays in delivering clinical decisions. To make precision diagnostics accessible, we introduce an integrated computational histopathology and adaptive nanopore sequencing workflow for next day CNS tumour diagnostics. METHODS We used CNS-CHiP- a multitask deep transfer learning model to predict key molecular alterations and methylation classification from H&amp;E stained CNS tumour slides. For further characterisation and subtyping, we used the predictions to formulate a custom panel for each patient. Targeted sequencing and analyses were performed using Rapid-CNS2- a custom neurooncology nanopore sequencing pipeline for parallel copy-number, mutational and methylation analysis that is flexible in target selection with no additional library preparation and can be initiated upon receipt of frozen sections. Sequencing was performed on a portable MinION or GridION. RESULTS We demonstrate our workflow on diagnostic samples received by the Department of Neuropathology, University Hospital Heidelberg. CNS-CHiP predicted multiple pathognomonic alterations (eg. IDH mutation, 7 gain/10 loss) with reasonable accuracy. This provided basic information regarding the tumor type instantly. Personalised panels enabled small target sizes, resulting in low sequencing time (up to 24h) and competitive costs. The GPU-accelerated bioinformatics pipeline reduced analysis time from &amp;gt; 24h to &amp;lt; 3h. CONCLUSIONS Our workflow harnessing histology-based molecular predictions to instruct targeted nanopore sequencing can be set up with low initial investment and has the potential to facilitate reporting of molecular results on the next day of sample collection. CNS-CHiP combined with Rapid-CNS2 thus aims to make CNS tumour diagnostics affordable and accessible to smaller hospitals and labs especially in low- and middle-income countries.
NCMP-18. NEUROLOGICAL SEQUELAE IN THE ID8 OVARIAN CANCER MOUSE MODEL: P38/JNK MAPK INHIBITION AS A POTENTIAL THERAPEUTIC FOR CANCER-RELATED COGNITIVE IMPAIRMENTS AND CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Authors: Naomi Lomeli, Martha Garcia, Donovan Argueta, Kalpna Gupta, Daniela Bota
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are neurological sequelae of platinum-based chemotherapy. To examine the contribution of cancer itself and additional neurological impairment with chemotherapy, we used the ID8 syngeneic ovarian cancer mouse model and assessed cognition and hyperalgesia +/- cisplatin treatment. We examined the effect of p38 and c-JUN N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) inhibition on cisplatin-induced neuronal damage. METHODS B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 m¬¬¬g/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. Cognition was assessed longitudinally at 69d by the open field test (OFT), novel object recognition (NOR) at 75d and 104d, and novel place recognition (NPR) at 106d post-ID8 implantation. Hyperalgesia was assessed at 113d. Primary mouse and rat hippocampal neurons were pre-treated with VX-745 or SP600125, followed by cisplatin, and neuronal morphology was assessed. RESULTS OvT+VEH mice had detectable abdominal tumors 90d post-implantation. At 75d, OvT+VEH and OvT+CIS had impairments in NOR, with discrimination ratios (DR)= 0.52, 0.51, respectively. OvT+VEH showed trending differences vs. OvT+CIS (DR=0.39, DR=0.62, p=0.079) on NOR on 104d, and impairments on NPR on 106d (DR=0.41, DR=0.63, p=0.03). Cisplatin decreased mechanical (p&amp;lt; 0.05) and cold hyperalgesia (p&amp;lt; 0.07, n.s.) in OvT+CIS vs. OvT+VEH. VX-745 and SP600125 pre-treatment in mouse and rat hippocampal neurons prevented cisplatin-induced dendritic branching and spine density loss (p&amp;lt; 0.05). DISCUSSION While cisplatin transiently increased anxiogenic behavior, cognitive impairments, and hyperalgesia in OvT+CIS, these deficits persisted longitudinally in OvT+VEH, suggesting ovarian cancer may evoke sensory and progressive neurocognitive deficits in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer mice +/- cisplatin, and whether VX-745 and SP600125 administration ameliorates CRCI/CIPN in this model.
EPCO-28. DOT1L AND PRC2 REGULATE A SHARED EPIGENETIC MECHANISM IN GLIOBLASTOMA AND MIXED LINEAGE LEUKEMIA
Authors: Samir Assaf, Danielle Bozek, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor, with a median survival of 15 months despite current treatments. We recently established that the epigenetic regulator Disruptor of Telomeric Silencing-1-Like (DOT1L) was essential for the growth of brain tumor stem cells (BTSCs), which are thought to underlie GBM tumor initiation and treatment resistance. Given the previously recognized importance of DOT1L histone methylation for the regulation of the similarly rare and aggressive childhood cancer, Mixed Lineage Leukemia (MLL), we interrogated for common mechanisms in both BTSCs and MLL cells, that overlap due to the epigenetic role of DOT1L. To gain a more detailed perspective of the importance of the DOT1L epigenetic mark in BTSCs, we performed a chemogenomic screen using the DOT1L inhibitor, EPZ-5676. Results from this screen revealed genes from transcriptional and epigenetic complexes required for a therapeutic response to DOT1L inhibition in BTSCs. Gene targeting approaches and growth assays further identified the Polycomb Repressive Complex 2 (PRC2) as a common determining factor for the growth response of both BTSCs and MLL cells following DOT1L inhibition. Furthermore, analysis of the chromatin accessibility changes regulated by DOT1L and PRC2 histone methylation identified both shared and unique epigenetic characteristics of GBM and MLL. The extent to which these shared mechanisms underpin the pathogenic process in these distinct diseases is being further investigated by assessing the divergence in transcriptional responses that emerge from this common epigenetic phenomenon. The findings from this study will provide insight into the importance of shared epigenetic mechanisms that underlie the tumorigenesis of unique cancers affecting the brain and blood.